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Radiation to Address Cells with Resistance to Targeted Therapies
Introduction
Thank you to member Craig for asking some excellent questions in response to my Highlights of 2011 webinar (http://cancergrace.org/lung/2012/03/30/qa-lc-highlights-weiss/#comment-9498 ). Thank you also to Dr. West, who emailed me to comment more on the idea of radiation for cells with acquired resistance.
We’ve spoken at length about EGFR and related mutations such as EML4/ALK and ROS1 on GRACE. For those who are not familiar with these subjects, I will refer you to my webinar for a summary on the most recent data on EGFR, EML4/ALK and ROS1:
(Parenthetically, we did also cover CT screening and optimal management of elderly patients at http://cancergrace.org/lung/2012/03/22/dr-weisss-highlights-in-lung-cancer-2011-ct-screening-optimal-management-of-elderly-patients-with-advanced-nsclc/ )
In the Q&A for this webinar that covered some of the existing approaches to resistance, Dr. West pushed me and asked if there was one that was particularly promising. Well, I’ve spent a ton of time thinking about this problem and have written a trial to attempt to address it. I couldn’t resist the bait and mentioned my trial. In this post, I’d like to review the rationale for the approach that I described and address Craig (and Dr. West’s) question about how appropriate this approach will be to new mutations, such as EML4/ALK and ROS1.
The Approach:
(click on image to enlarge)
The basic idea is to take patient whose cancer has grown on tarceva, do cyberknife to the spots that have grown to eliminate the resistant clones, then continue using tarceva for the rest of the cancer that has shown evidence for ongoing sensitivity to tarceva.
Dr. Le, Radiation Oncologist from Stanford, on Radiation Options for Early Stage NSCLC
Dr. Quynh Le, radiation oncologist and Professor at Stanford University, was kind enough to participate in our NSCLC Patient Education Forum. She spoke on the topic of emerging treatment options using radiation for early stage NSCLC. The new work she’s describing on stereotactic body radiation therapy (SBRT) is looking promising enough that it’s being considered increasingly as a very strong choice for people with localized lung cancer but who aren’t good candidates for surgery or are disinclined to pursue it. In fact, much of the debate in the lung cancer community is about whether SBRT appears compelling enough to be considered as a viable alternative to surgery even in patients who are fine candidates for resection.
The podcast and additional materials from her presentation are here:
Q Le Radiation for Early Stage NSCLC Audio Podcast
q-le-radiation-for-early-stage-nsclc-figures
q-le-radiation-for-early-stage-nsclc-transcript
Some passages of the program may be a little difficult to follow, so please use the transcript if you need to clarify parts. You can also ask questions here, for clarification or follow-up. I hope you find it helpful.
Podcast: Play in new window | Download (0.0KB) | Embed
Video Podcast Presentation on Locally Advanced NSCLC
Ask and ye shall receive! The leading requiest for a video podcast presentation was for a summary of the subject of locally advanced, unresectable stage III NSCLC. Here you go:
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Sorry it’s a little rushed, but it’s a struggle to do a topic justice with a 10 minute limit (the most YouTube accepts). In the future, we’ll try to divide bigger topics into two podcasts if it’s going to require cramming into a 10 minute interval. It may help for you to have the images and transcript available, so here they are:
Locally Advanced NSCLC vodcast images
Tales from the Clinic: Surgery after Chemo/Radiation
In prior posts I’ve described the special circumstance of a Pancoast tumor, which is a tumor at the top of the lung that tends to grow into the spine, ribs, and sometimes the nerves going to the arm. These cases are a major challenge because surgery is often something to consider, because they often grow locally more than speading to the rest of the body, but surgery can be a special challenge because the vertebrae are generally not considered to be resectable. But some of our cases test the limits of what might be resectable, especially since our center has an orthopedic surgeon who has done special training at a surgical center in Paris that does surgeries on the spine that are not supposed to be surgically manageable. This has led our surgeons to to try some amazing and ambitious combined lung and spine operations on a few patients with lung cancer who would not have undergone surgery almost anyplace else. Is that a good thing? The patients who have done well think so, but this work has raised some tough questions, as illustrated by the case of Julia K.
Julia was a 56 year-old server in a restaurant in Maui with a history of smoking for about 30 years but having quit about a decade before having increasing left shoulder and back pain. As is typical for a waitress with presumed musculoskeletal back and shoulder pain, this didn’t send off any alarm bells, and her pain continued and worsened for about 4 months before her doctor ordered a chest x-ray, which was very abnormal and led to a CT, which revealed an approximately 6 cm tumor invading her second and 3rd ribs on her left toward the back, with what appeared to potentially be invasion or at least encroachment on the vertebrae:
On learning this, she left Maui and returned to her childhood home of Rochester, Minnesota (big change from Maui, I imagine), where she had an extensive workup at the Mayo Clinic. Her biopsy showed a poorly differentiated NSCLC (no histology reported), and she was subsequently decided to move to Seattle to be with and receive support from her best friend, who lived here. She was referred to me and the rest of our team for management.
Interview with Dr. Vivek Mehta, Radiation Oncologist: Early Stage and Locally Advanced NSCLC
As we move forward in our audio/visual odyssey, we’re going to add audio interviews with experts in various aspects of cancer care. The first of these is from our own Vivek Mehta, who sat down with me to go over current radiation approaches for patients with early stage NSCLC, as well as management locally advanced NSCLC.
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And along with that is the transcript for this interview, here. Dr. Vivek Mehta Interview I Transcript
We’re still trying to get the optimal setup, which this isn’t. There’s some background noise, but it’s all audible. And things will only get better. There are a few more in the works.
What I Really Do: Locally Advanced, Unresectable NSCLC
The setting of unresectable, stage IIIA or IIIB NSCLC (without a malignant pleural effusion) is currently one for which what we feel is best for the patient isn’t necessarily something for which we have good evidence. For fit patients, there is a strong consensus that giving concurrent chemo with radiation provides a modestly but consistently higher cure rate than giving chemo and radiation sequentially. But that concurrent chemoradiation plan lasts for only 6-8 weeks, but whether there’s more we should be doing, or what we should do, is entirely unclear.
As described in a prior post, several studies in the last decade have shown that about two cycles or 6-8 weeks of weekly chemotherapy along with about 60-66 Gray of radiation over 6-8 weeks is associated with the best survival results we’ve seen in unresectable, locally advanced NSCLC (somewhere in the 20% range long-term, and a median of about 16-18 months). There are two main approaches in North America for the chemotherapy. Some use the SWOG approach that showed very promising early results (prior post here), giving cisplatin and etoposide. The other very common alternative that is widely used in a community setting is weekly carboplatin/taxol. Until very recently had relatively little published experience to support it, but in the last few years now has been included in a few trials that demonstrate survival in the same ballpark as what we routinely see with cisplatin-based chemo: examples include RTOG trials such as described in a prior post and another abstract.
Integrating Alimta and Cetuximab in Locally Advanced NSCLC
As a follow-up to my last post on the appeal of developing new regimens for combining with radiation in treatment of locally advanced unresectable NSCLC, I wanted to highlight work being done by the Cancer and Leukemia Group B (CALBG), one of the major cancer cooperative research groups in the US. As I mentioned previously, we’ve had difficulty developing widely accepted alternatives for the few chemo regimens commonly used in combination with concurrent radiation — primarily cisplatin/etoposide or weekly carbo/taxol. Some experts feel that weekly carbo/taxol has a shortcoming in that it is given at a more frequent but lower dose than the “full dose” every three week regimen, and the lower dose may have very little activity against micrometastatic cancer cells traveling throughout the bloodstream. For that reason, it may be preferable to give full, “systemic dose” chemo at least at some point during treatment for locally advanced NSCLC, and giving it during radiation could allow you to treat a person for both local cancer in the chest(disease you can see and treat directly, with radiation, while chemo bolsters the radiation — called chemosensitization) and distant disease outside of the radiation field. But there are relatively few chemo regimens that can be given safely at full “systemic” doses with radiation concurrently. The CALGB lung cancer committee has been working on a new regimen that incorporates a regimen of carboplatin and alimta one day every three weeks at full dose, with radiation, an approach that could potnetially be enthusiastically adopted in the lung cancer community as a newer and more convenient alternative if it looks as good or better than our older standards.
Now that there is evidence from early safety/feasibility studies that chest radiation can be given along with full dose alimta every three weeks along with carboplatin (abstract here) or cisplatin (abstracts here and here), CALGB developed a trial to test the activity and safety of carbo/alimta/RT followed by alimta “consolidation”, or the same strategy with erbitux added throughout, both during the radiation and afterward, with the alimta consolidation (abstract here). The trial design is as shown here:
Introducing Erbitux and Other Agents into Treatment of Locally Advanced NSCLC: RTOG Experience
While there have been new agents introduced and rapidly changing standards in advanced NSCLC, another 40% of patients with NSCLC have locally advanced (stage III) NSCLC, many of whom with disease that is not resectable but is potentially curable with agressive chemo and radiation. Last year’s ASCO meeting included results that strongly suggested that consolidation taxotere after 6-7 weeks of concurrent chemo and radiation may not add a benefit, and in an important trial by the Hoosier Oncology Group (affectionately known as the HOG), the best treatment was with just two cycles of cisplatin/etoposide chemotherapy along with radiation (as detailed in a prior post).
Many oncologists, myself included, have been reluctant to accept that just two cycles of chemo and seven weeks radiation are really enough to treat stage IIIB disease, which is clearly more of a threat than stage II NSCLC, for instance, and for which we standardly give four cycles of platinum-based chemo. Most US-based oncologists give either two cycles of cisplatin/etoposide with concurrent chest radiation, or weekly low-dose carboplatin/taxol for about 7 weeks while a patient is getting radiation, and it’s a bit unsettling to think that either there aren’t potential improvements to be made by adding new agents, either to replace some of our older standards or to add along with the chemo/radiation concurrently or as a different consolidation therapy. Cisplatin/etoposide/RT has been used now for both limited SCLC and locally advanced NSCLC for 20 years, so we’re all impatient to see new agents take their place and define some new standards.
Consolidation Radiation to Residual Chest Disease After Chemo for Extensive SCLC?
Here’s a situation in which I learned something from the questions raised by people here online. A handful of people with extensive disease small cell lung cancer (ED-SCLC) in the last year or two have mentioned receiving radiation for areas of residual apparent disease after receiving initial chemotherapy. I had noted that I had never done this and didn’t really see a clear rationale for pursuing a local treatment like radiation for a disease that has already declared itself as spreading throughout the body. But while there is no good evidence to say that radiation should be included after chemo, it is actually an open question, and there are some recommendations that say it’s something to consider under certain conditions.
The question of whether radiation should be added routinely to chemo for ED-SCLC was the subject of several very old studies from 20-30 years ago, and they didn’t show any clear benefit. However, radiation has changed a lot in that time, and in truth, several studies that compared chemo alone to chemo/RT were so small that they couldn’t say anything meaningful. In fact, there was a single study published based on the combined efforts of groups in Germany and Japan (abstract here) that randomized patients who experienced a complete response (no evidence of disease) outside of the chest and either a complete or partial response in the chest to either additional chemo alone after platinum/etoposide chemo, or chemo and aggressive chest radiation. The results looked more facorable for the patients who received radiation in addition to chemo, although only 109 patients were included in the relevant analysis. Again, this was only in the patients who had a complete response and no evidence of cancer outside of the chest after initial chemo. As you might expect, radiation was associated with sometimes significant esophagitis (painful inflammation of the esophagus).
Unfortunately, I don’t believe there’s been any further assessment of this question presented or published in the last decade. Based on the rather scant evidence but some hint of a possible benefit, the American College of Chest Physicians has included in their evidence-based guidelines about managing SCLC (abstract here) that, while not a clear recommendation, it is reasonable to offer chest radiation to patients with ED-SCLC who have a complete response outside of the chest and a complete or partial response within the chest, acknowledging that this is a concept based on pretty weak evidence.
Still, I wanted to highlight this because it represents a situation in which I learned something new that will probably change my treatment approach, based on what people here described. I want to ensure that I’m open to new information and can not be wedded to just doing things the way I’ve previously approached them, if there is more information. In this case, the little information available goes back a long ways, but it suggests that it could be appropriate to be open-minded to the idea that “consolidation radiation” to the chest might be helpful even for extensive SCLC.
Limited Resection vs. Radiation for Marginal Patients with Early Stage NSCLC
The standard of care for at least stage I and II NSCLC is surgery, sometimes followed by chemotherapy. We know, however, that not every patient who presents with early stage NSCLC is healthy enough to pursue surgery, whether due to general age-related or other illnesses, or due specifically to a low pulmonary reserves, usually from years of smoking. As our population ages and the median age of newly diagnosed lung cancer patients crosses 70, this is likely to become a bigger issue, but unfortunately we haven’t got a lot of information on the best way to treat sicker patients who are on the border of safety and feasibility for standard surgery for lung cancer. I’ve described in a prior post that there is some evidence that older patients may do as well with a limited, smaller resection (the different types of surgery described in another prior post). Otherwise, we know that many patients who are marginal for surgery are recommended to receive radiation instead. Perhaps not surprisingly, the survival results of patients with early stage NSCLC who receive radiation are not as favorable as the results with surgery, stage for stage.
While one explanation for this may be that surgery is just more effective in curing early stage lung cancer than radiation, there are some confounding issues. One is that it’s not uncommon for the patients who undergo surgery to be found to have involved lymph nodes or other findings at surgery that increase their stage. In contrast, patients who never undergo surgery may have those same lymph nodes or other findings but never be properly staged pathologically, so they would potentially be considered a stage I patient but really be a stage II or III if surgery had been done and could detect occult cancer involvement. Probably more important, though, is the fact that the vast majority of patients who receive radiation have been recommended to not receive surgery, presumably because they were felt to have too many competing risks and to not be healthy enough to pursue the rigors of surgery. Therefore, we’re really talking about two different populations of patients, one likely appreciably healthier than the other, so it shouldn’t be surprising that the excluded group does less well.
There are some novel radiation approaches that have been developed over the past several years that may serve as alternatives to surgery for some patients with early stage NSCLC, so it would be great to really know how advantageous surgery is vs. a non-surgical approach in marginal resection candidates. What would really answer the question is a randomized trial of borderline patients to receive either surgery or radiation. Well, dream on, because that’s not happening. At least in the US, it’s nearly impossible to imagine doctors and patients accepting a randomization to either surgery or non-surgery — it’s very difficult to do such randomizations in a system where people are used to having much more control. Continue reading
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